Epigenetic regulation of human telomerase reverse transcriptase promoter activity during cellular differentiation

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<jats:title>Abstract</jats:title><jats:p>The human telomerase reverse transcriptase (<jats:italic>TERT</jats:italic>) gene is transcriptionally inactivated in most differentiated cells but is reactivated in the majority of cancer cells. To elucidate how <jats:italic>TERT</jats:italic> is inactivated during differentiation, we applied <jats:italic>all‐trans</jats:italic> retinoic acid (ATRA) to induce the differentiation of human teratocarcinoma (HT) cells and human acute myeloid leukemia (HL60) cells. We first showed that <jats:italic>TERT</jats:italic> promoter activity decreased rapidly, which preceded a gradual loss of endogenous telomerase activity following ATRA induction. To elucidate the underlying mechanisms of the reduced <jats:italic>TERT</jats:italic> promoter activity during differentiation, we performed epigenetic studies on the <jats:italic>TERT</jats:italic> promoter and found a progressive histone hypoacetylation coupled with a gradual accumulation of methylated cytosines in the <jats:italic>TERT</jats:italic> promoter. We also observed that the <jats:italic>TERT</jats:italic> promoter was less methylated in pluripotent HT cells than in multipotent HL60 cells throughout a 12‐day differentiation process. This origin‐dependent epigenetic change was also confirmed in histone acetylation studies, indicating that the <jats:italic>TERT</jats:italic> promoter was more resistant to deacetylation in HT cells than in HL60 cells. Taken together, our results demonstrate synergistic involvement of DNA methylation and histone deacetylation in the down‐regulation of <jats:italic>TERT</jats:italic> promoter activity that may be dependent on the origin of the cell types, and they add new insight into the way telomerase activity may be regulated during differentiation. © 2004 Wiley‐Liss, Inc.</jats:p>

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